Glomerular disease remains a leading cause of kidney failure. Injury to the glomerular mesangial cell (MC) is associated with increased proliferation and apoptosis, and the balance of these processes determines the cell number. We and others have previously shown that cell proliferation is ultimately controlled in the nucleus by cell cycle regulatory proteins. Proliferation requires the activation of specific cyclin dependent kinases (CDK). To prevent unregulated proliferation, CDK-inhibitors bind to and inactivate CDKs. In this grant proposal we will now show that cell cycle proteins also have a critical role in regulating cell apoptosis, and that this is independent of proliferation. The studies in the first Specific Aim are designed to show that CDK2 causes MC apoptosis in response to certain forms of injury, that blocking CDK2 activity will prevent cell death, and the effects of CDK2 are distinct from its role in cell proliferation. We will examine potential mechanisms explaining this effect, and suggest that an unregulated CDK2 activity leads to a catastrophic progression through the cell cycle that results in cell death rather than proliferation. In the second Specific Aim, we will show that a novel function of the CDK-inhibitor, p27 which is present in high levels in normal cells, is to protect cells from death. We will also test the hypothesis that p27 determines the onset, magnitude and threshold to apoptosis, which is mediated by restraining CDK2 activation. Finally, the roles of CDK2 and p27 in MC apoptosis will be tested by inducing experimental glomerular disease in normal mice, and in mice that lack the p27 gene, and in certain experiments, CDK2 activity will be pharmacologically inhibited. Our ultimate goal is to show novel roles for specific cell cycle proteins in glomerular disease, so that specific therapeutic strategies can be developed to reduce glomerular injury.